Distinct Sex-Specific Characteristics of Apoe Deficient and Ldlr Deficient Mice in Atherosclerosis: Implications for Model Selection and Therapy Development

The progression of cardiovascular disease shows significant sexual dimorphism: although females generally develop the disease later in life, they exhibit a higher age-related incidence than males. While current studies have separately reported sex differences in atherosclerotic development in Apoe−/− and Ldlr−/−, a comparative assessment of these sex-specific characteristics across both models is lacking. This study therefore aimed to assess the influence of sex on atherosclerosis using both Apoe−/− and Ldlr−/− mice. Eight-week-old mice were fed an atherogenic ALMN diet for 20 weeks to promote plaque development. We performed comprehensive analyses of: (1) systemic metabolic parameters (lipid profile, glucose metabolism); (2) atherosclerotic burden (whole aorta and aortic sinus plaque area); and (3) plaque composition (necrotic core size, collagen content, macrophage infiltration) in mice of both sexes. As a result, male mice showed higher lipid levels, worse glucose tolerance, and reduced insulin sensitivity compared to females in both models. Apoe−/− mice showed minimal sex differences in atherosclerosis with a trend toward increased plaque size in females. Plaque composition did not differ significantly between sexes in Apoe−/− mice. In contrast, Ldlr−/− males exhibited greater whole aortic plaque burden than females, yet plaque stability also remained similar across sexes. This comparative analysis of two widely used murine atherosclerosis models reveals genotype-dependent sexual dimorphism. This study underscores the importance of considering the distinct sex-specific characteristics of Apoe−/− and Ldlr−/− mice when selecting animal models for exploring atherosclerosis pathomechanisms as well as effective pharmacotherapies, and further supports the necessity of developing sex-specific therapies.